A Novel Modular Polymer Platform for the Treatment of Oral and Head And Neck Carcinoma

1. A Novel Modular Polymer Platform for the Treatment of Oral and Head And Neck Carcinoma MAIE A. ST. JOHN, MD, PHD Department of Head & Neck Surgery David Geffen School of Medicine, UCLA Jonsson Comprehensive Cancer Center

2. The Preschool Years

3. The IncredibleEgg . . .

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6. However . . .

7. The Oreo . . .

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11. Why Oral and Head and Neck Cancer? • PhD years • surgery and cancer • anatomy intricate and personal

12. OSCC • Aggressive surgical resection cornerstone of treatment • Disfiguring Quality of Life

13. Surgery Can Be Disfiguring

14. OSCC • Despite advances in surgical techniques and chemoradiation: • Past 30 years, 5 year survival rate with advanced SCC poor (20-30%) • 50% of patients fail primary management • Recur at primary site or lymphatics • Presence of metastatic SCCA in LNs: correlates with 50% decrease in survival

15. OSCC • Standard of care: Surgical Salvage • Resectability • Proximity to vital structures (ICA, skull base)

16. Recurrent Oral and Head & Neck SCCA • Palliation: • Radiation Therapy: • Many patients receive RT as definitive or adjuvant therapy • Retreatment a challenge • Chemotherapy: • Systemic Toxicity • Efficacy • Poor quality of life • New advances needed for effective treatment

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18. The Polymer Platform • The Clinical Problem: • patients with advanced or recurrent OSCC: • tumor is fixed to the underlying vital structures • surgery becomes cytoreductive rather than ablative and curative. • Polymer Platform:  • most oral and head and neck cancers and their cervical metastatic nodes are clinically accessible • local treatment with a polymer matrix will have significant clinical applications. • treat recurrent tumors refractory to multimodality therapy, or as a concurrent treatment with radiotherapy to augment its response.

19. The Polymer Platform • Polymer technology for Drug Delivery evolved since 1990: • Tx: neoplasms, brain disorders, infections • Harness the power of the polymer system further • Beyond its capacity as a drug delivery system

20. Goals The polymer system as a modular platform • Facile application • Serve as a mechanical barrier to early metastasis and angiogenesis • Incorporate a radiosensitizer • Incorporate a radioopaque tracer (tantalum) • Evaluate recurrence by volume averaging on CT scan • Function as a platform to deliver immunomodulators

21. Polymer Platform Design First week After 4-6 weeks Cisplatin Cisplatin CCL-21 Initial Release Micro-porous gel, <2 wks degradation Intermediate Release Macro-porous matrix, 4-6 wk degradation Degradation of the Impermeable Backing Film Impermeable Backing FilmNon-porous, radiopaque, > 4-6 wks degradation

22. The Polymer Platform as a Mechanical Barrier • Prevent initial metastasis while cells are fragile • Prevent ingrowth of vasculature (angiogenesis)

23. The Polymer Platform in Monitoring Tumor Recurrence • Tantalum • Volume averaging

24. The Polymer Platform as a Radiosensitizer • Delivery of a lethal dose of RT to a tumor while sparing nearby tissues • Chemotherapeutic agents as radiosensitizers (Cisplatin) • Enhanced tumor cell killing without increased normal tissue toxicity • Maximizing drug concentration in tumor microenvironment and minimizing systemic drug distribution

25. The Polymer Platform as a Radiosensitizer • Advantages of polymer over Brachytherapy • Eliminates radioprotection issues for patient and their family • Psychosocial: daily activities not limited

26. The Polymer Platform in Immunomodulator Delivery • Increase the efficiency of tumor cell killing by the host’s immune system • Combinations of immunomodulators and drugs • identify ideal synergistic combinations • dissect the mechanisms of interrelated pathways

27. Immunomodulators • HNSCC patients: • Documented local immunosuppression: T cells and NK cells • Gene therapy: largely remains limited • Major limitation for clinical use of cytokines: • Lack of an effective protocol for local and sustained release.

28. CCL21 • CCL21 (secondary lymphoid chemokine, SLC): • recruit DC, T, NK and NKT cells • distinctly advantageous because of its capacity to elicit a type I cytokine response in vivo • Our group demonstrated previously that CCL21 administered intratumorally elicits potent antitumor responses in murine cancer models • substantiated by other groups in lung and colon cancer models • In addition to its immunotherapeutic potential, CCL21: potent angiostatic effects • additional support for its use in cancer therapy.

29. Import of the polymer system as a modular system • Modularplatform can serve to limit the recurrence of OSCC by attacking the cancer cells in several ways. • a chemotherapeutic agent: effectively kill tumor cells in the proximity of the polymer application • platform to deliver immunomodulators • Elegant approach to future dosing modifications and device improvements • Incorporate changes into one layer without altering the chemical-physical properties of the other layer • Robust design • Enable dissection of underlying mechanisms of immune activation and expansion, • design additional strategies to block the inactivation and death of the cytotoxic effectors

30. The Problem in a Nutshell How do we make the future better?

31. Hypotheses • The local delivery of chemotherapeutic agents will enhance tumor reduction • The local delivery of immunomodulators will increase the efficiency of tumor cell killing by the host’s immune system • The modular nature of our polymer platform will allow us to customize it for individual patient tumors

32. Specific Aims • Specific Aim 1.Determine the efficacy of the polymer as a platform for chemotherapeutic delivery in combination with Radiation Therapy • Specific Aim 2.Determine the efficacy of the polymer as a platform for immunomodulator delivery in the presence of Radiation Therapy • Specific Aim 3.Customize the Polymer for Individual Patient Tumors

33. Specific Aims • Specific Aim 1.Determine the efficacy of the polymer as a platform for chemotherapeutic delivery in combination with Radiation Therapy Specific Aim 1a. Determine the release kinetics of cisplatin under the influence of ionizing radiation. Specific Aim 1b. Assess the in vivo efficacy of the Chemotherapeutic Layer of the polymer, in combination with radiation treatment Cisplatin

34. Experimental Model Day 0 tumor cell injection Day 7-10 (tumor 1 cm2) debulksurgery / polymer monitoring

35. Cisplatin Polymer Effectively Reduces the Growth OSCC in Mouse Model (Hu, 2012)

36. Cisplatin Secreting Polymer Enhances the Efficacy of Radiation Therapy A B

37. Decreased RT is required in the presence of Cisplatin Polymer 2 8 6 1 4 5,7 3

38. Specific Aims • Specific Aim 2.Determine the efficacy of the polymer as a platform for immunomodulator delivery in the presence of Radiation Therapy Specific Aim 2a. Determine the release kinetics of the immunomodulators (CCL21) under the influence of ionizing radiation. Specific Aim 2b. Assess the in vivo efficacy of the bilayer polymer (Chemotherapeutic and Immunomodulator layers), in combination with radiation treatment.

39. DC-CCL21 Polymer Dendritic Cells Tumor

40. DC-CCL21 cultured in the polymer is capable to producing CCL21 in vitro Time dependent continuous release of CCL21 from DC-CCL21 in polymer

41. CCL21 release kinetics from polymer

42. Polymer-based DC-CCL21 treatment inhibits tumor growth

43. DC-CCL21 treatment inhibits EMT in squamous cell tumors

44. DC-CCL21 Decreases Tregs in tumors Animals receiving DC-CCL21 polymer therapy exhibited a significant increase in the frequency of CD4+ T cell and CD11c+ dendritic cells, as well as a marked decrease in CD4+CD25+ regulatory T cells infiltrating the tumor site.

45. Concomitant CCL21 and cisplatin secreting polymer further reduced tumor burden Blank polymer CCl21 polymer Cisplatin polymer Cisplatin / CCL21 polymer

46. Summary of Findings • The local delivery of Cisplatin significantly reduces tumor burden and decreases the dosage of RT required. • The local delivery of CCL21 significantly reduces tumor burden by increase the efficiency of tumor cell killing by the host’s immune system • Polymers with a combination of Cisplatin and CCL21 further reduce tumor burden. • The modular nature of our polymer platform will allow us to customize it for individual patient tumors

47. Specific AimsFuture Directions • Specific Aim 3.Customize the Polymer for Individual Patient Tumors • Modular polymer platform • We will use the DCTD (Division of Cancer Treatment and Diagnosis) approved oncology drugs to screen against a panel of established and primary (obtained from our patients) human oral cancer cell lines. Tumor

48. Custom Made Polymers • Patient has biopsy done and tumor screened for its drug sensitivity profile • Immune boosting agents and specific drugs that work against that patient’s specific tumor are layered onto the polymer • The polymer is applied at the time of surgery

49. Clinical Trial • optimized and validated our cisplatin polymer in mouse model • plan a prospective trial in patients with unresectable SCC • 10-15 patients with end stage unresectable oral or head and neck cancer. • debulking surgery • polymer application • low dose of RT • GMP grade polymers that are identical from batch to batch. • modular nature of this polymer platform • incorporate changes into one layer without altering the chemical-physical properties of the other layer. • intervention that warrants larger scale research efforts or multi-site clinical trials.

50. “My husband, Rick, says I’m in the business of putting myself out of business. If that happens in my lifetime, I would be thrilled!”